A basic challenge for drug delivery is to develop approaches for delivering molecules or complexes to cells of a patient in a way that is efficient and safe. To this end, a variety of methods and routes of administration have been developed to deliver pharmaceuticals that include small molecular drugs and biologically active compounds such as peptides, hormones, proteins, and enzymes to their site of action. Parenteral routes of administration include intravascular (intravenous, intra-arterial), intramuscular, intraparenchymal, intradermal, subdermal, subcutaneous, intratumor, intraperitoneal, and intralymphatic injections that use a syringe and a needle or catheter. The blood circulatory system, while providing systemic spread of a pharmaceutical, doesn't readily enable delivery of many molecules or complexes to parenchymal cells outside the blood vessels.
The controlled release of pharmaceuticals after their administration is also under intensive development. Polyethylene glycol and other hydrophilic polymers have provided protection of pharmaceuticals in the blood stream by preventing interaction with blood components, opsonization, phagocytosis and uptake by the reticuloendothelial system, thereby increasing the circulation time of the pharmaceutical. For example, the enzyme adenosine deaminase has been covalently modified with polyethylene glycol to increase its circulatory time and persistence in the treatment of patients with adenosine deaminase deficiency. Pharmaceuticals have also been complexed with a variety of biologically-labile polymers to delay their release from depots. Typical examples of biodegradable and non-degradable sustained release systems included copolymers of, respectively, poly(lactic/glycolic) acid (PLGA; Jain et al. 1998) and ethylvinyl acetate/polyvinyl alcohol (Metrikin & Anand 1994).
Transdermal routes of administration have been effected by patches and ionotophoresis. 5 Other epithelial administration routes include oral, nasal, respiratory, and vaginal. These routes have attracted interest for the delivery of peptides, proteins, hormones, and cytokines, which are typically administered parenterally using needles. For example, the delivery of insulin via oral or nasal routes is attractive for patients with diabetes mellitus. Capsules and pH-sensitive hydrogels have been developed for oral delivery (Hu et al. 1999, Lowmanet al. 1999).
Liposomes are also used as drug delivery vehicles for low molecular weight drugs such as adriamycin, an anticancer agent, and amphotericin B for systemic fungal infections. pH-sensitive polymers have been used in conjunction with liposomes for the triggered release of an encapsulated drug. For example, hydrophobically modified N-isopropylacrylamide-methacrylic acid copolymer can render regular egg phosphatidyl chloline liposomes pH-sensitive due to pH-dependent interaction of grafted aliphatic chains with lipid bilayers (Meyer et al. 1998).
A number of techniques have also been explored for delivery of DNA encoding therapeutic genes to cells in mammals, a process called gene therapy. These techniques include direct injection of naked DNA into tissue, especially muscle, the “gene gun”, electroporation, the use of viral vectors, and cationic liposome and polymers. These techniques however, suffer from delivery to too few cells and/or toxicity. While highly effective in vitro, cationic DNA-containing complexes generally have been of limited success in vivo becuase their large size and positive charge has an adverse influence on biodistribution of the complexes.